Intranasal instillation techniques are used to deliver various substances to the upper and lower respiratory tract (URT and LRT) in mice. Here, we quantify the relative distribution achieved with ...intranasal delivery of a nonabsorbable tracer, (99m)Tc-labeled sulfide-colloid. Relative distribution was determined by killing mice after instillation and quantifying the radioactivity in dissected tissues using gamma scintigraphy. A significant effect of delivery volume on relative distribution was observed when animals were killed 5 min after instillation delivered under gas anesthesia. With a delivery volume of 5 microl, no radiation was detected in the LRT; this increased to a maximum of 55.7 +/- 2.5% distribution to the LRT when 50 microl were delivered. The majority of radiation not detected in the LRT was found in the URT. Over the course of the following 1 h, radiation in the LRT remained constant, while that in the URT decreased and appeared in the gastrointestinal tract. Instillation of 25 microl into anesthetized mice resulted in 30.1 +/- 6.9% distribution to the LRT, while only 5.3 +/- 1.5% (P < 0.05) of the same volume was detected in the LRT of awake mice. Varying the body position of mice did not affect relative distribution. When using intranasal instillation, the relative distribution between the URT and LRT and the gastrointestinal tract is heavily influenced by delivery volume and level of anesthesia.
Macrophages can display a number of distinct phenotypes, known collectively as polarized macrophages. The best defined of these phenotypes are the classically-activated, interferon gamma (IFNγ)/LPS ...induced (M1) and alternatively-activated, IL-4 induced (M2) macrophages. The goal of this study is to characterize macrophage-Chlamydia interactions in the context of macrophage polarization. Here we use Chlamydia muridarum and murine bone-marrow derived macrophages to show Chlamydia does not induce M2 polarization in macrophages as a survival strategy. Unexpectedly, the infection of macrophages was silent with no upregulation of M1 macrophage-associated genes. We further demonstrate that macrophages polarized prior to infection have a differential capacity to control Chlamydia. M1 macrophages harbor up to 40-fold lower inclusion forming units (IFU) than non-polarized or M2 polarized macrophages. Gene expression analysis showed an increase in 16sRNA in M2 macrophages with no change in M1 macrophages. Suppressed Chlamydia growth in M1 macrophages correlated with the induction of a bacterial gene expression profile typical of persistence as evident by increased Euo expression and decreased Omp1 and Tal expression. Observations of permissive Chlamydia growth in non-polarized and M2 macrophages and persistence in M1 macrophages were supported through electron microscopy. This work supports the importance of IFNγ in the innate immune response to Chlamydia. However, demonstration that the M1 macrophages, despite an antimicrobial signature, fail to eliminate intracellular Chlamydia supports the notion that host-pathogen co-evolution has yielded a pathogen that can evade cellular defenses against this pathogen, and persist for prolonged periods of time in the host.
Abstract Objectives Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with an increased risk of osteoporosis and fractures. TNF inhibitors have been used to treat AS, but their ...effect on bone is unclear. Thus, we conducted a meta-analysis to study the effect of TNF inhibitors on spine and hip BMD in patients with AS. Methods Two authors independently searched MEDLINE and PubMed for longitudinal studies that had assessed the effect of TNF inhibitors on BMD in patients with AS. Studies with a minimum follow-up period of 1 year were included. Results Seven longitudinal studies and one randomized control trial were included, with a total of 568 AS patients (mean age range of 36–48 years and disease duration of 9–17 years). Lumbar spine BMD increased by 5.1% (95% CI: 4.0–6.1%, p = 0.00000) after 1 year of treatment with TNF inhibitors and by 8.6% (95% CI: 6.8–10.3%, p < 0.00001) after 2 years. Significant improvements in total hip BMD were also noted after 1 1.8% (1.0–2.5%) and 2 years 2.5% (1.9–3.0%). Compared to baseline, femoral neck BMD remained stable after 1 year 0.7% (−0.8% to 2.2%), p = 0.34. No significant heterogeneity was noted amongst the included studies. Conclusions TNF inhibitors can increase lumbar spine and total hip BMD and maintain femoral neck BMD for up to 2 years in patients with AS. More research is needed to assess the effect of TNF inhibitors on bone quality and fracture risk.
Summary
We describe variation across geographical regions of England in operations undertaken following presentation of hip fracture and in 30-day mortality. Some significant geographic variation in ...30-day mortality was observed particularly for patients with trochanteric hip fractures and warrants further investigation of other aspects of post-hip fracture care
Introduction
Mortality after hip fracture has improved considerably in the UK over recent decades. Our aim here was to describe geographical variation in type of operation performed and 30-day mortality amongst patients in England with hip fracture.
Methods
The National Hip Fracture Database was used to carry out a prospective cohort study of nearly all over-60 year olds with hip fracture in England. These data were linked to Hospital Episode Statistics (HES), allowing us to explore regional variation in the operations performed for three fracture types (intracapsular, trochanteric and subtrochanteric), and use logistic regression models adjusted for demographic and clinical factors to describe associated 30-day mortality.
Results
NHFD recorded data for 64,211 patients who underwent surgery in England during 2017. Most had an intracapsular (59%) or trochanteric fracture (35%), and we found significant geographical variation across regions of England in use of total hip replacement (THR) (ranging from 10.1 to 17.4%) for intracapsular fracture and in intermedullary nailing (ranging from 14.9 to 27.0%) of trochanteric fracture. Some geographical variation in mortality amongst intracapsular fracture patients was found, with slightly higher mortality in the East of England (adjusted odds ratio aOR: 1.22, 95% CI: 1.02–1.46). Trochanteric fractures showed slightly more variation, with higher 30-day mortality (aOR: 1.40, 95%CI: 1.05–1.88) in the East of England and significantly lower mortality in the North East (aOR: 0.65, 95%CI: 0.46–0.93).
Conclusions
We have identified regional differences in operation type and 30-day mortality amongst hip fracture patients in England. The relationship between surgical approach and mortality has been explored, but the extent to which differential mortality reflects variation in approach to medical assessment, anaesthesia and other aspects of care warrants further investigation.
A fracture of the hip is the most common serious orthopaedic injury, and surgical site infection (SSI) is one of the most significant complications, resulting in increased mortality, prolonged ...hospital stay and often the need for further surgery. Our aim was to determine whether high dose dual antibiotic impregnated bone cement decreases the rate of infection.
A quasi-randomised study of 848 patients with an intracapsular fracture of the hip was conducted in one large teaching hospital on two sites. All were treated with a hemiarthroplasty. A total of 448 patients received low dose single-antibiotic impregnated cement (control group) and 400 patients received high dose dual-antibiotic impregnated cement (intervention group). The primary outcome measure was deep SSI at one year after surgery.
The rate of deep SSI was 3.5% in the control group and 1.1% in the intervention group (p = 0.041; logistic regression adjusting for age and gender). The overall rate of non-infective surgical complications did not differ between the two groups (unadjusted chi-squared test; p > 0.999).
The use of high dose dual-antibiotic impregnated cement in these patients significantly reduces the rate of SSI compared with standard low dose single antibiotic loaded bone cement. Cite this article: Bone Joint J 2016;98-B:1534-1541.
Over the past 5 years, advances in high-throughput techniques and studies involving large cohorts of patients have led to considerable advances in the identification of novel genetic associations and ...immune pathways involved in ankylosing spondylitis (AS). These discoveries include genes encoding cytokine receptors, transcription factors, signalling molecules and transport proteins. Although progress has been made in understanding the functions and potential pathogenic roles of some of these molecules, much work remains to be done to comprehend their complex interactions and therapeutic potential in AS. In this Review, we outline the current knowledge of AS pathogenesis, including genetic risk associations, HLA-B27-mediated pathology, perturbations in antigen-presentation pathways and the contribution of the type 3 immune response.
The spatial variation of productivity across farm fields can be classified by delineating site-specific management zones. Since productivity is influenced by soil characteristics, the spatial pattern ...of productivity could be caused by a corresponding variation in certain soil properties. Determining the source of variation in productivity can help achieve more effective site-specific management. The objectives of this study were (i) to characterize the spatial variability of soil physical properties across irrigated corn (Zea Mays L.) production fields and (ii) to determine if soil physical properties could explain the variability in productivity between site-specific management zones. The study was conducted over three study sites in northeastern Colorado. The soil properties measured were bulk density, cone index, surface soil color, organic C, texture, sorptivity, and surface water content. A multi-response permutation procedure was used to test for significant differences among soil properties between management zones. Box plots of soil physical properties were created for each management zone within each study site to determine if trends in soil physical properties corresponded to the productivity potential of the management zones. Overall, this study showed that soil physical properties exhibited significant spatial variability across production fields. The trends observed for the measured soil physical properties corresponded to the productivity potential of the management zones. Utilizing site-specific management zones could help manage the in-field variability of yield-limiting soil physical properties.
Decreased ATP correlates with intraocular pressure exposure in the optic nerves of mice with glaucoma. To understand what underlies this energy deficit, we examined mitochondria in the myelinated ...optic nerve axons of the DBA/2J mouse, a model of glaucoma secondary to iris pigment disease, and the DBA/2(wt-gpnmb) control strain.
Mitochondrial length, width, surface area, and health status were measured in 30 electron microscopic fields within the myelinated portion of optic nerves from DBA/2J and DBA/2(wt-gpnmb) mice at 3, 6, and 10 months of age. Protein was isolated from optic nerve for analysis of PINK1, Parkin, LC3-I and -II, and lysosome-associated membrane protein 1 (LAMP1) by Western blot.
The number of mitochondria in DBA/2J optic nerve was increased, and they had significantly smaller surface area. Mitochondria in DBA/2J were closer to the axolemma, more spatially isolated, and their cristae were more disrupted at every age group as compared to DBA/2(wt-gpnmb). Autophagosomes were significantly increased in DBA/2J optic nerve at all ages. Protein analysis showed higher LC3-II to LC3-I ratio in aged DBA/2J optic nerve than in DBA/2(wt-gpnmb). PINK1 and Parkin levels were not statistically different across age groups. LAMP1 was significantly decreased in the aged DBA/2J optic nerve.
Decreased surface area, combined with reduced oxidative capacity in mitochondria from the aged DBA/2J axon, indicate that mitochondrial pathology may contribute to the energy deficit in glaucomatous optic nerve. Though autophagosomes were increased in DBA/2J optic nerve, the increased mitochondria and decreased LAMP1 suggest deteriorating mitochondria are not being efficiently recycled by mitophagy.
Despite over ten years of work into the low-cost electrowinning of Ti direct from the oxide, the reduction sequence of TiO2 pellets in molten CaCl2 has been the subject of debate, particularly as the ...reduction pathway has been inferred from ex situ studies. Here, for the first time white beam synchrotron X-ray diffraction is used to characterize the phases that form in situ during reduction and with a arrow right 4100I14m resolution. It is found that TiO2 becomes sub-stoichiometric very early in reduction, facilitating the ionic conduction of O ions, that CaTiO3 persists to nearly the end of the process and that, finally, CaO forms just before completion of the process. The method is quite generally applicable to the in situ study of industrial chemical processes. Implications for the industrial scale-up of this method for the low-cost production of Ti are drawn.
Objective: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. Methods: 277 patients who had participated in a previous ...randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. Results: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. Conclusion: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.
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